1. Technical Field
The present disclosure relates to a method for the synthesis of N-substituted carboxylated pyridinium compounds.
2. Description of the Related Art Pyridinium compounds are of interest in, for example, drug design and as general intermediates for organic syntheses, such as in natural product synthesis. Certain substituted pyridinium compounds are useful in the synthesis of NAD or NAD analogs, respectively. Additionally, certain heteroaryl substituted pyridinium compounds have been studied in relation to solvatochromism.
Currently, the standard method for the synthetic production of substituted pyridinium compounds includes alkylation of pyridine derivatives. However, this reaction is only convenient when using primary alkyl halides. When secondary or tertiary alkyl halides are used, elimination occurs as an unwanted side reaction and yields are generally low. Moreover, when the alkylation is performed with alkyl halides having a halogen atom attached to an asymmetric carbon atom, racemization may occur during the nucleophilic displacement reaction.
Zincke salts may be prepared by reacting a pyridinium compound with 2,4 dinitro halobenzol preferably with 2,4 dinitrochlorbenzol and 2,4 dinitrobrombenzol.
As is apparent from the above description, the activation reagents presently used in production of substituted pyridinium compounds are toxic, explosive, and/or otherwise hazardous and are therefore limited to small scale research applications. Additionally, while there have been sporadic attempts at performing Zincke reactions in an ecofriendly manner, for example by using microwave assisted synthesis, such attempts still rely on explosive dinitrophenyl compounds and are not capable of being scaled up without taking expensive precautionary measures.
It is also known that various 2-alkylaminopentadienimin derivatives react with NH4OAc or primary amines (R—NH2) under acidic conditions to form the corresponding 3-alkylated pyridines, respectively, 1-R-3-alkyl-substituted pyridinium compounds. The required 2-alkylaminopentadienimin compounds are accessible from N-tertbutylimino derivatives of aldehydes, deprotonated with LDA and reacted with vinamidinium chloride.
However, the utility of this method is severely limited. Reactive groups, such as ester functions, may not be introduced in position 2 of the aminopentadienimin system, which, for example, would be a prerequisite for the synthesis of nicotinic acid ester derivatives.
As such, there is a need for a new and improved method of synthesis of N-substituted pyridium compounds which avoids hazardous activation reagents and which overcomes other problems known in the art.